https://doi.org/10.

1590/0004-282X20190188
VIEW AND REVIEW

Medical management after subthalamic

stimulation in Parkinson’s disease:
a phenotype perspective
Manejo medicamentoso após estimulação subtalâmica na doença de Parkinson:
uma perspectiva fenotípica
Ana Paula BERTHOLO1, Carina FRANÇA1, Wilma Silva FIORINI2, Egberto Reis BARBOSA1, Rubens Gisbert CURY1

ABSTRACT
Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment that improves motor fluctuations, dyskinesia, and
tremor in Parkinson’s disease (PD). After the surgery, a careful electrode programming strategy and medical management are crucial,
because an imbalance between them can compromise the quality of life over time. Clinical management is not straightforward and depends
on several perioperative motor and non-motor symptoms. In this study, we review the literature data on acute medical management after
STN DBS in PD and propose a clinical algorithm on medical management focused on the patient’s phenotypic profile at the perioperative
period. Overall, across the trials, the levodopa equivalent daily dose is reduced by 30 to 50% one year after surgery. In patients taking high
doses of dopaminergic drugs or with high risk of impulse control disorders, an initial reduction in dopamine agonists after STN DBS is
recommended to avoid the hyperdopaminergic syndrome, particularly hypomania. On the other hand, a rapid reduction of dopaminergic
agonists of more than 70% during the first months can lead to dopaminergic agonist withdrawal syndrome, characterized by apathy, pain,
and autonomic features. In a subset of patients with severe dyskinesia before surgery, an initial reduction in levodopa seems to be a more
reasonable approach. Finally, when the patient’s phenotype before the surgery is the severe parkinsonism (wearing-off) with or without
tremor, reduction of the medication after surgery can be more conservative. Individualized medical management following DBS contributes
to the ultimate therapy success.
Keywords: deep brain stimulation; medical management; Parkinson’s disease; phenotype; subthalamic nucleus.

RESUMO
A estimulação cerebral profunda do núcleo subtalâmico (ECP NST) é um tratamento estabelecido para doença de Parkinson (DP), que leva
à melhora das flutuações motoras, da discinesia e do tremor. Após a cirurgia, deve haver uma estratégia cuidadosa de programação da
estimulação e do manejo medicamentoso, pois um desequilíbrio entre eles pode comprometer a qualidade de vida. O gerenciamento clínico
não é simples e depende de vários sintomas motores e não motores perioperatórios. Nesta revisão, discutimos os dados da literatura
sobre o tratamento clínico agudo após a ECP NST na DP e propomos um algoritmo clínico baseado no perfil fenotípico do paciente no
período perioperatório. Em geral, nos estudos clínicos, a dose diária equivalente de levodopa é reduzida em 30 a 50% um ano após a
cirurgia. Em pacientes que recebem altas doses de medicações dopaminérgicas ou com alto risco de impulsividade, recomenda-se redução
inicial do agonista dopaminérgico após a ECP NST, para evitar síndrome hiperdopaminérgica, particularmente a hipomania. Por outro lado,
uma rápida redução de agonistas dopaminérgicos em mais de 70% durante os primeiros meses pode levar à síndrome de abstinência do
agonista dopaminérgico, com apatia, dor e disautonomia. Em pacientes com discinesia grave antes da cirurgia, é recomendada redução
inicial na dose de levodopa. Finalmente, quando o fenótipo do paciente antes da cirurgia é o parkinsonismo grave (flutuação motora) com ou
sem tremor, a redução da medicação após a cirurgia deve ser mais conservadora. O tratamento médico individualizado após a ECP contribui
para o sucesso final da terapia.
Palavras-chave: estimulação encefálica profunda; manejo medicamentoso; doença de Parkinson; fenótipo; núcleo subtalâmico.

1
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Centro de Distúrbios do Movimento, São Paulo SP, Brazil.
2
Universidade de São Paulo, Instituto de Psiquiatria, Centro de Psicologia, São Paulo SP, Brazil.
Ana Paula BERTHOLO https://orcid.org/0000-0003-2150-9300; Carina FRANÇA https://orcid.org/0000-0001-8036-2439;
Wilma Silva  FIORINI https://orcid.org/0000-0003-1214-9526; Rubens Gisbert CURY https://orcid.org/0000-0001-6305-3327
Correspondence: Rubens Gisbert Cury; Av. Dr. Enéas de Carvalho Aguiar, 255 / 5º andar / sala 5.084 - Cerqueira César; 05403-900 São Paulo SP, Brazil;
E-mail: rubens_cury@usp.br
Conflict of interest: There is no conflict of interest to declare.
Received on August 27, 2019; Received in its final form on October 16, 2019; Accepted on November 6, 2019

230
 Parkinson’s disease (PD) is a progressive neurodegen-
erative disorder, which affects several regions of the cen-
tral and peripheral nervous system, leading to both motor
and non-motor manifestations along the disease course1,2.
Surgical treatments for PD, specifically stereotactic ablations
(conventional thalamotomy and pallidotomy), were devel-
oped before the introduction of levodopa, and reemerged
later as a means to overcome difficulties in the medical man-
agement of motor complications, due to the dopaminergic
therapy in patients with advanced PD1.
Deep brain stimulation (DBS) has been shown to have
several advantages compared to traditional lesions, including
adaptability, reversibility, and the possibility to be performed
bilaterally in the same surgical session3. The subthalamic
nucleus (STN) is the preferred target among centers and is
an established and effective form of treatment that improves
motor fluctuations, dyskinesia, and quality of life in well-
selected patients with PD4,5.
The success of deep brain stimulation does not rely only
on the surgery itself, but also on a whole process, that encom-
passes several preoperative and postoperative issues. There are
key factors in the success of the therapy, starting with the rigor-
ous and standardized selection of patients and meticulous sur-
gical planning to optimize the placement of electrodes. After
the procedure, electrode programming strategies and medical
management, in both the early and the long-term follow-up,
are crucial, given that an unbalancing between them can com-
promise motor and non-motor functions over time2,4.
Medical management is not straightforward, because
the phenotype of patients undergoing surgery is variable6.
Some patients have more dyskinesia, tremor, or motor fluc-
tuations, or a combination thereof. Additionally, the range of
non-motor symptoms varies among candidates, and this may
influence how medications are managed2. Therefore, the way
we change the medication after surgery should be tailored to
the individual characteristics of each patient.
In view of the importance of standardized medical man-
agement after surgery, the present study aims to:
• Evaluate literature data on acute medical manage-
ment after DBS in PD.
• Propose a clinical algorithm on medical manage-
ment focused on the patient's phenotypic profile at the peri-
operative period.
SEARCH STRATEGY AND SELECTION CRITERIA
References for this review were identified by searches on
PubMed, published up to August 2019, and references from rel-
evant articles. We searched for the terms “hyperdopaminergic
syndrome”, “hypodopaminergic syndrome”, “apathy”, “cognition”,
“dementia”, “depression”, “dopamine agonist”, “impulse control
disorders”, “psychosis”, “dyskinesia”, “medication”, “levodopa”
and “non-motor symptoms” in combination with the terms
“deep brain stimulation” and “Parkinson’s disease”. There were
no language restrictions. The final reference list was generated
based on the relevance to the topics covered in this article.
WHO ARE THE PATIENTS REFERRED FOR DBS?
Patient eligibility for DBS is determined by standardized
evaluation in specialized movement disorder centers, using a
comprehensive selection process, including a levodopa chal-
lenge test, brain imaging, and assessment of neuropsycholog-
ical and psychiatric functions, with the purpose of achieving
the best clinical results and minimizing side effects and com-
plications6-8. Parkinsonian motor signs, such as OFF symp-
toms, dyskinesias, and tremor are the major complaints of the
patients refereed for DBS surgery6-8. Pre-operative levodopa-
responsiveness has been universally accepted as the sin-
gle best outcome predictor for response to DBS; with the
exception of levodopa-unresponsive tremor, all motor signs
that improve with levodopa prior to surgery are expected to
improve postoperatively8,9.
Besides the impairment in motor functions, patients
undergoing DBS often present a range of non-motor symp-
toms. In a large cohort of PD patients referred to DBS, half
of them fulfilled diagnostic criteria for hyperdopaminergic
behavioral disorders, encompassing dopamine dysregulation
syndrome and impulse control disorders10,11. Patients under-
going DBS present bothersome disease-related symptoms
(motor and non-motor symptoms) associated with high
doses of dopaminergic drugs (total levodopa equivalent daily
dose - LEDD-greater than 1000 mg), frequently including a
dopamine agonist11,12. As detailed below, when we “add” the
STN stimulation to patients who are already under high doses
of dopaminergic drugs, there is an over-inhibition of the STN
activity13. This inhibition, in turn, may ‘release the horses’ and
culminates in a worsening of dyskinesias and increases the
risk of hyperdopaminergic syndrome, such as impulse con-
trol disorders during the short-term period after surgery1-14.
Thus,  a careful and individualized medical management
strategy is needed to ‘hold the horses’.
THE SUBTHALAMIC NUCLEUS IN THE
CONTEXT OF DEEP BRAIN STIMULATION
The STN is a small nucleus that projects fibers to the pal-
lidum and to the substantia nigra and uses glutamate to medi-
ate its function15. Deep brain stimulation interferes with the
function of the STN and reduces its output, alleviating parkin-
sonian symptoms (orthodromic effect). In addition, DBS exerts
its activity by modulating afferent terminals, including those
from the cortex (antidromic effect). The stimulation of afferent
Bertholo AP et al. Drug management after DBS in Parkinson’s disease 231
 axons could antidromically activate several cortical areas in a
retrograde manner, influencing distal sites6. Most  of the cor-
tical afferents to the STN arise from the primary motor cor-
tex and supplementary motor area and innervate the dorsal
aspects of the nucleus (motor part of STN)16. The limbic ven-
tromedial portion of the STN receives fibers from the prelim-
bic-medial orbital areas of the pre-frontal cortex17. Electrode
contacts used for chronic DBS in PD are supposed to target the
dorsolateral part of the STN (Figure 1), but limbic spread of the
current could lead to neuropsychiatry symptoms18.
PRACTICAL RECOMMENDATIONS IN
THE ACUTE PHASE FOLLOWING STN DBS
The concerns that clinicians should be aware of after sur-
gery are:
• The amount of medication that should be reduced
(total LEDD).
• Which medication, in a logical order, should
be tapered.
Several studies have shown that the LEDD19 is reduced by
30 to 50% one year after surgery14-21 (Table 1 defines the ‘total’
and the ‘dopamine agonist’ LEDD). One study demonstrated
that the major modifications in medication dosage occurred
during the initial postoperative period - the first 6 months14.
In this study, the total LEDD was reduced by 53.4% compared
to baseline at 6 months and 47.9% at 3 years14. They evalu-
ated 150 patients and showed that 56% of patients were on
monotherapy at 6 months and 41.3% at 3 years. Furthermore,
9.3% patients were free from medication at 6 months, and 7%
were free at 3 years14. The complete discontinuation of medi-
cation is usually avoided because the lack of dopamine in the
limbic system can lead to apathy and depression2,14. The order
of medication tapering will depend on the clinical phenotype
before the surgery and the patient’s profile following the sur-
gery. Details are provided in the following sections.
Orange: STN; Red: Red Nucleus; Green: Globus Pallidus Internus
47
Figure 1. Upper view of electrodes implanted in a patient
with Parkinson’s disease located in the dorsal part of
subthalamic nucleus.
232 Arq Neuropsiquiatr 2020;78(4):230-237
Dyskinesias
Levodopa-induced dyskinesia (LID) occurs in nearly all
patients with PD after 10 years of chronic dopaminergic
treatment, it is secondary to early treatment with high doses
and chronic pulsatile stimulation of dopamine receptors22.
In the extreme, patients can cycle between disabling dys-
kinesias during the “ON” state and disabling parkinsonism
during the “OFF” state23. Risk factors for the development of
dyskinesias are young-onset PD, female gender, high UPDRS
part II scores at baseline, lower weight, and high dose of
levodopa23. Striatal denervation and subsequent structural
alterations of post-synaptic dopaminergic transmission are
necessary for LID to develop24.
STN DBS does not have an appreciable antidyskinetic
effect and can even induce dyskinesias, which thwarts an
increase in stimulation during programming1. In most cases,
when stimulation-induced dyskinesia occurs it has been
interpreted as a good prognostic sign, indicating that the
optimal lead location has been achieved25,26. There are experi-
ments suggesting that glutamate neurotransmitter release
may underpin stimulation induced dyskinesia, but the exact
mechanisms remain unknown27.
Dyskinesia reduction has been consistently reported
after STN implantation, due to the reduction of postopera-
tive dopamine replacement therapy1, in particular levodopa.
Russmann et al. found that LID was reduced by 74% after 21
months of STN DBS, along with a reduction in antiparkinso-
nian medication during this time22.
In a prospective study of 91 patients, a robust improve-
ment in all motor signs in the OFF condition (the per-
centage of time with good mobility and no dyskinesia and
mean dyskinesia score) was observed. Six months after
DBS, 74% of patients were without dyskinesia in “ON”
state compared to 27% at baseline, and 7% of patients
were with dyskinesias in “ON” state compared to 23% at
Table 1. Protocol for calculating levodopa equivalent daily dose
for antiparkinsonian agents.
Parkinsonian Drug Conversion factor
Immediate release L-dopa dose x1
Controlled release L-dopa dose x 0.75
Entacapone x 0.33
Pramipexole x 100
Ropinirole x 20
Rotigotine x 30
Selegiline x 10
Rasagiline x 100
Amantadine x1
Total LEDD is the sum of all drugs (Actual total daily dose x Conversion factor).
Dopamine agonist (DA) LEDD represents the Pramipexole, Ropinirole or
Rotigotine daily dose x Conversion factor.
baseline. The  mean reduction in the LEDD was approxi-
mately 60%28,29. It became clear that the reduction in dyski-
nesia could be attributed, at least partly, to the reduction
in the levodopa dosage28. A comprehensive meta-analysis
of 921  patients who underwent STN DBS between 1993
and 2004 noted an average reduction in dyskinesia of
69.1%, with an average reduction in LEDD of 55.9%28,30.
Vingerhoets et al. evaluated 20 patients with PD with
motor fluctuations and dyskinesia, who underwent bilateral
STN DBS. The medication was reduced by 79% and was com-
pletely withdrawn in 10 patients. Fluctuations and dyskinesia
showed an overall reduction of 90%, disappearing completely
in patients without medication31.
In patients referred for DBS treatment due to severe dyski-
nesia, an initial reduction in levodopa (mainly the plasmatic
peak) soon after the surgery seems to be reasonable and can
be considered as the best approach. It is worth mentioning
that although the DBS stimulation is usually kept turned off
during the first weeks after surgery, a microlesion effect is a
commonly observed phenomenon after the electrode inser-
tion and mimics the DBS stimulation effect32. The microlesion
effect results from a transient damage of the STN and usually
lasts 3‒4 weeks32.
In patients who maintain dyskinesias, even after a reduc-
tion of levodopa following DBS, other strategies may be con-
sidered, such as: a concomitant reduction of dopaminergic
agonist, introduction of amantadine and/or clozapine, and
also programming techniques (not the aim of this article),
such as titrating of the stimulation by small steps (0.1‒0.2
volts every week), bipolar stimulation, and stimulation of the
more dorsal contacts. This later approach allows the current
to spread into the dorsally adjacent lenticularis fasciculus,
which exerts an effect similar to that of pallidal stimulation
and ultimately suppresses dyskinesia, mimicking the anti-
dyskinetic effect of globus pallidus internus stimulation1.
An infrequent but nonetheless potential complication
of STN DBS is a permanent stimulation-induced dyskinesia
following the surgery. A small subset of patients experiences
troublesome dyskinesia after STN DBS, despite optimal pro-
gramming and medication adjustments (called ‘brittle’ dyski-
nesia)25. Young onset of PD may play a role in the genesis of
this post-STN DBS ‘brittle’ dyskinesia. Other risk factors, such
as longer disease duration, longer duration of levodopa ther-
apy, and female patients with a low body weight have been
suggested, although the number of patients reported so far is
small27,28. The emergence of this troublesome dyskinesia post-
STN DBS is challenging. Rescue GPi DBS can be effective in
‘brittle’ dyskinesia and was previously reported25.
Hyperdopaminergic syndrome
During the few days immediately following surgery,
patients usually experience a mild euphoria, hyperactivity,
and increased motivation32. Overall, this “disinhibition” is
overlooked by patients and their relatives, and it naturally
improves within a few weeks. However, in a few patients, a
more robust hyperdopaminergic syndrome may arise, and
generally results from a combination of the lesioning effect
of the electrode, the high frequency stimulation itself (which
has an inhibitory effect over the nucleus), and a high dopami-
nergic load.
The STN is a key player in the inhibitory control of com-
plex motivated behavior2 and is directly involved in our
decision making, providing a “NoGo” signal that suppresses
responses13. Accordingly, some evidence from pre-clinical
studies shows that STN lesions impair the response selection
processes, and lead to premature responding in high-conflict
choice selection paradigms13. Taken together, in the acute
phase after surgery, the synergistic activity of both high fre-
quency stimulation and the persistent effect of dopaminergic
drugs over-inhibit the STN, releasing the brake and disinhib-
iting behavior2.
Hyperdopaminergic syndrome following the surgery can
worsen if the current spreads to the ventral-medial regions (lim-
bic part) of the STN34. DBS-induced mania/hypomania appears
to occur in 4% of patients35, but this number increases to 82%
with ventromedial electrode placement36. Therefore, slow titra-
tion of the stimulation and avoidance of the most medial and
inferior contacts are recommended (Figure 2).
Reducing dopaminergic medication load might lead to
an improvement in behavioral features. In patients with a
high risk of hyperdopaminegic syndrome (male sex, young
age at onset, previous history of ICD, and dopamine agonist
LEDD over 150 mg) an initial reduction of dopaminergic ago-
nists - even before the surgery - is recommended. The amount
of reduction is not established, but a reduction of 15‒30% of
dopamine agonists LEDD during the first months follow-
ing the surgery seems reasonable (which represents the
Pramipexole, Ropinirole or Rotigotine daily dose x Conversion
factor - see Table 1). An aggressive reduction (more than 70%
in dopamine agonists LEDD) can be associated with severe
apathy and depression and should be discouraged37. In those
Orange: STN sensorimotor region; Yellow: STN limbic region47.
Figure 2. Electrode reconstruction illustrating the volume
of tissue activated (circumferential red circle around the
electrode) into the sensorimotor region of the STN (dorsal
part). Note the yellow region (limbic region) in the anterior part
of the nucleus. The spread of the current to this region could
lead to neuropsychiatry symptoms.
Bertholo AP et al. Drug management after DBS in Parkinson’s disease 233
 patients not taking dopamine agonists, the initial levodopa
reduction should be preferable over other drugs, because of
its psychostimulant effects111. A short course of clozapine or
quetiapine may be necessary in some cases during the first
weeks following surgery, along with neuropsychologist evalu-
ation and cognitive behavioral therapy2.
It is important to highlight that a dopaminergic drug
decrease does not instantly lead to a reduction in the behav-
ioral effects, because the drugs also have long-term effects35.
In the long-term, the reduction of dopaminergic medication
leads to progressive disappearance of their long-term effects
and to desensitization38.
Despite being uncommon, the presence of hyperdopami-
nergic syndrome after STN DBS can be reduced if a detailed
preoperative assessment is performed. In our center, the
neuropsychology team routinely applies the Ardouin Scale
of Behavior in Parkinson’s Disease (ASBPD)15, which uses a
structured, standardized interview designed to detect and
quantify a wide range of neuropsychiatric symptoms in
PD15,39. The scale assesses ‘behavioral addictions’ to classify
repetitive behaviors found in patients with PD, including
impulse control disorder, punding, and excessive hobbyism.
Every item is rated on a five-point scale from 0 (absence of
disorder or change compared to usual behavior) to 4 (severe
behavioral disorder) by accounting for the severity and the
frequency of the disorder compared to premorbid usual
functioning and its psychosocial effect. When any item on
the ASBPD scores 3 or 4 the patient is not referred for DBS
until the symptom is compensated.
Finally, psychosis, characterized by short-lasting tran-
sient hallucinations and delusions, are described shortly after
surgery. In these cases, the first medications to be generally
reduced or discontinued are the anticholinergic drugs, fol-
lowed by amantadine, dopaminergic agonists, catechol-O-
methyltransferase inhibitor (COMTi), monoamine oxidase
inhibitor (MAOi), and, lastly, levodopa. The prescription of
antipsychotics for short-term use can be necessary2.
The other side of the coin: Hypodopaminergic syndrome
Apathy and depression are common neuropsychiatric
disorders in PD, with the prevalence reaching 50% for depres-
sion, and from 17 to 70% for apathy39. These symptoms can
be observed at all stages of the disease, but are predominant
at its onset or when it is undertreated39. Postoperatively, apa-
thy and depression may emerge and have been attributed to
direct stimulation effects of the STN for apathy or of adja-
cent zones for depression, but most importantly, due to inad-
vertent overreduction of levodopa and dopamine agonists
inducing dopamine withdrawal syndromes24-40.
Apathy
Apathy is one of the most common symptoms found in
PD and is defined as a lack of motivation accompanied by
reduced goal-directed cognition, behavior, and emotional
234 Arq Neuropsiquiatr 2020;78(4):230-237
involvement11. It may be observed at all stages of PD, in
isolation or more frequently in association with dementia,
depression, or anxiety41. Postoperative apathy is frequently
associated to anxiety or depression and seems to be the
tip of the iceberg of a larger spectrum of hypodopaminer-
gic symptoms42.
Apathy occurs after a mean of 4‒7 months following
DBS1 and is associated with rapid reduction of dopaminer-
gic therapy, which leads to a postoperative deactivation of
dopaminergic receptors within the mesocortical and meso-
limbic pathways1. Thobois and some colleagues showed that
after a forceful 82% reduction of dopaminergic medication
within 2 weeks after surgery, half of patients developed apa-
thy. Furthermore, postoperative apathy has been considered
in the spectrum of dopamine withdrawal syndrome (DAWS).
A PET study at baseline revealed that the greater the meso-
corticolimbic dopaminergic denervation, the higher the odds
of developing apathy after surgery43.
Apathy following STN DBS responds to dopamine ago-
nist treatment43. Czernecki et al. showed that apathy dra-
matically improved with ropinirole, a D2 and D3 dopami-
nergic agonist, in all but one of the 8 patients who became
apathetic after complete withdrawal of dopaminergic med-
ication following STN stimulation44. In the present study,
the average score on the Starkstein Apathy scale showed an
improvement of 54% (±24%), and the improvement in mood
was not correlated to the effect on apathy44. Thobois et al.
also showed that piribedil, another D2/D3 dopaminer-
gic agonist, significantly alleviates postoperative apathy in
patients with PD after STN DBS42.
Because of the risk of hyperdopaminergic syndrome,
dopamine load should not be reduced sharply after sur-
gery, since this could lead to patients becoming apathetic.
The presence of apathy after surgery can “block” the benefi-
cial effect of DBS on motor symptoms. Whereas clinicians are
happy with the motor outcome, the patient’s global impres-
sion does not change after surgery or, in some cases, it even
worsens. This is why apathy should be detected after surgery
and treated early on with dopaminergic drugs to prevent
postoperative depression with suicidal risk2,43. Practical rec-
ommendations indicate that, overall, dopaminergic medica-
tions, especially dopamine agonists, should be reduced dur-
ing the months following STN DBS, but a reduction of more
than 70%, or a complete discontinuation, must be avoided.
Depression
In patients with bilateral chronic STN stimulation,
depressive features improved, remained unchanged, or
even worsened compared to the preoperative condi-
tion20,45. Postoperative improvement of depression might
result from a psychological response to the alleviation
of disabling motor symptoms or from the effects of STN
stimulation on neural circuits involved in mood20,45. On the
other hand, suicidal tendencies have been reported in
some patients with PD after STN DBS1. Occurrence of sui- Dyskinesia STN DBS
cide has been linked to hypodopaminergic features sec- Note: The optimization
ondary to acute post-surgical withdrawal of medications, of the DBS program
Initially, reduce may be necessary
which, as discussed, is a common practice in the initial levodopa in some cases:
-titrating of the
phase of DBS treatment46. We recommend a very close fol- stimulation by
low-up and repetitive psychological assessment, if needed, Consider add small steps
(0.1-0.2 volts
amantadine or clozapine
throughout the first postoperative year to detect a delayed every week)
-bipolar configuration
onset hypodopaminergic syndrome, which requires cau- -stimulation of the
Reduction of dopamine
tious as to the re-introduction of dopaminergic medica- agonists, COMTi, MAOi more dorsal contacts

tions and antidepressant treatment2.

Hyperdopaminergic STN DBS
syndrome

Rigidity, bradykinesia,
ICD/DDS Hypomania Psychosis
tremor and motor fluctuations
STN DBS improves rigidity and bradykinesia by 63 and
52%, respectively, 12 months after surgery1. With the addition Reduce dopamine agonists* and Reduction/withdrawal
avoid ventro-medial spread of of anticholinergic drugs,
of dopaminergic replacement therapy, these improvements the current (lower contacts) amantadine, dopamine,
agonists, MAOi, levodopa
increased to 73 and 69%, respectively1. Regarding the tremor,
STN stimulation may produce an improvement of 86% in the
first year after surgery1. When the patient’s phenotype before
Consider adding quetiapine or clozapine
surgery is the severe parkinsonism (wearing-off) with or
without tremor, the reduction of the medication can be more
Hypodopaminergic
STN DBS
conservative. In such cases, the add-on of DBS plus medica- syndrome

tion are beneficial. Overall, we keep the levodopa unchanged

Apathy Anxiety Depression
and decrease the dopaminergic agonist when the DA LEDD
is greater than 150 mg, due to potential neuropsychiatric side
effects, as previously discussed. Sequentially, when the stimu-
Overreduction of dopamine agonist after surgery
lation reaches a stable value, there is a gradual reduction in (over than 70% in DA LEDD)?

anticholinergic medications, followed by COMTi, amanta- Yes No

dine, and MAOi14.
Increase the dopamine Check for the DBS settings:
agonist dosage current spreading to the ventral-medial
region of the STN (limbic part)**
FINAL REMARKS
Consider antidepressant treatment

In patients referred for DBS surgery, it is important to

Rigidity, bradykinesia, STN DBS
evaluate the patient's main phenotype at baseline, because tremor and motor fluctuations
it directly influences the drug management soon after
surgery (Figure 3 summarizes the algorithm). This assess- Conservative reduction

ment of motor and non-motor symptoms, which predom-

inate in each individual, allows a more individualized Progressive
withdrawal
reduction in the amount of dopaminergic drugs and a log- Anticholinergic
ical sequence of reduction to minimize potential postop-
COMTi
erative risks. Hyperdopaminergic and hypodopaminergic
Amantadine
syndromes, together with severe dyskinesia, are the most
MAOi
challenges issues31.
A multidisciplinary approach with the systematic Dopamine agonist
Keep levodopa
assessment of non-motor dopamine-dependent symp- Slow reduction (avoid reduction
of more than 70% in DA LEDD)
toms is essential to screen for changes in motivation
and mood, and to manage and prevent hypodopaminer- STN DBS: Subthalamic nucleus deep brain stimulation; COMTi/: catechol-O-
methyltransferase inhibitor; MAOi: monoamine oxidase inhibitor; ICD: impulse
gic and hyperdopaminergic episodes2. The reduction in control disorder; DDS: dopamine dysregulation syndrome; DA LEDD:
dopaminergic drugs afforded by STN DBS, and the con- dopamine agonist levodopa equivalent daily dose. *Overreduction can lead to
dopamine agonist withdrawal syndrome. **Although the limbic spread of the
sequent striatal desensitization, enable long term rever- current usually leads to hyperdopaminergic syndrome, negative symptoms,
such as apathy can happen and dramatically improve after DBS adjustment.
sal, not only of dyskinesia but also of hyperdopaminergic
Figure 3. Algorithm for medical management in the acute
behaviors. However, an abrupt drastic reduction in dopa- phase after subthalamic stimulation, according to the most
minergic drugs (in case of either disabling dyskinesia or prevalent patient’s phenotype.

Bertholo AP et al. Drug management after DBS in Parkinson’s disease 235

 pathologic hyperdopaminergic syndrome) may lead to
complications ranging from isolated apathy up to a full-
blown hypodopaminergic syndrome, highlighting apathy
as the core symptom in association with anxiety, depres-
sion, and pain, in various combinations2.
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